Alzheimer's disease (AD) is a progressive degenerative disease of the central nervous system characterized clinically by dementia and neuropathologically by the presence of numerous senile plaques and neurofibrillary tangles. AD is typically a disease of the elderly, afflicting up to 6% of those aged 65 years and up to 20% of 80 years olds. This is termed late onset AD. In addition, a small number of pedigrees have been described wherein the disease is inherited as an autosomal dominant with age dependent penetrance. Most commonly, the age of onset of the disease is below 60 years in these families. This is termed early onset AD. Genetic factors have been implicated in both early and late onset AD.
At least three different genetic loci that confer inherited susceptibility to this disease have been identified.
The .epsilon.4 (112CysArg) allele of the apolipoprotein E (ApoE) gene located on chromosome 19 is associated with AD in a significant proportion of cases with late onset. Strittmatter et al., Proc. Nat'l. Acad. Sci. USA 1993, 90:1977-1981; Saunders et al., Neurology 1993, 43:1467-1472. Inheritance of this allele has also been reported to lower the age of onset in a dose dependent manner. Corder et al., Science 1993, 261:921-923. Conversely, inheritance of the apolipoprotein E .epsilon.2 allele appears to confer a decreased risk of developing AD. Corder et al., Nature Genet. 1994, 7:180-184. While the biochemical mechanism of these effects is still unclear, there are significantly increased numbers of A.beta. deposits in the brains of patients having one or two .epsilon.4 alleles. Schmechel et al., Proc. Nat'l. Acad. Sci. USA 1993, 90:9649-9653; Hyman et al., Proc. Nat'l. Acad. Sci. USA 1995, 92:3586-3590.
Mutations in the gene for the .beta.-amyloid precursor protein (.beta.APP) on chromosome 21 have been found in a small number of families with disease onset before 65 years of age. Goate et al., Nature 1991, 349:704-706; Chartier-Harlin et al., Nature 1991, 353:844-846; Murrell et al., Science 1991, 254:97-99; Karlinsky et al., Neurology 1992, 42:1445-1453. These disease-causing mutations have been modelled in transfected or primary cultured cells and shown to lead to altered proteolytic processing of .beta.APP in a way that favors production of its amyloidogenic and potentially neurotoxic A.beta. fragment. Further, transgenic overexpression of one mutant .beta.APP has resulted in the first mouse model of AD, in which age-linked cerebral deposition of A.beta. is accompanied by neuronal, astrocytic and microglial pathology. Games et al., Nature 1995, 373:523-527.
A third locus (AD3) has been mapped by genetic linkage studies to chromosome 14q24.3 which may account for up to 70% of early-onset autosomal dominant AD. Schellenberg et al., Science 1992, 258:668-670; St. George-Hyslop et al., Natur Genet. 1992, 2:330-334; Van Broeckhoven et al., Natur Genet. 1992, 2:335-339. The AD3 locus is associated with the most aggressive form of this disease (onset 30 to 60 years of age) and it has been suggested that mutations at this locus put into effect a biologically fundamental process leading to AD. Sherrington et al., Nature 1995, 375:754-760.
A novel gene with five missense mutations in seven pedigrees segregating early-onset, autosomal dominant AD at the AD3 locus was recently cloned. Sherrington et al., Nature 1995, 375:754-760. This gene has been called S182. Analysis of the nucleotide sequences of the S182 transcript revealed heterozygous nucleotide substitutions in the reverse transcriptase-polymerase chain reaction products from affected members of six large pedigrees. Each of the nucleotide substitutions occurred within a putative open reading frame of the S182 transcript and are predicted to change the encoded amino acid at the following positions (numbering FAD4 and Torl.l; HisArg codon 163 in pedigree 603; AlaGlu at codon 246 in pedigree FAD1; LeuVal at codon 286 in pedigree FAD2; and CysTyr at codon 410 in pedigrees FAD3 and NIH2. of all the nucleotide substitution cosegregated with the disease in their respective pedigrees, none were seen in asymptomatic family members aged more than 2 standard deviations beyond the mean onset, and none were present on 284 chromosomes from unrelated neurologically normal subjects drawn from comparable ethnic origins. Sherrington et al., Nature 1995, 375:754-760.
A number of other mutant S182 genes have now been identified. These mutants are useful in the diagnosis of early-onset AD and in evaluating agents which may be useful for the treatment of this disease.